This application is in response to RFA-DA-04-014, which calls for research to identify, evaluate, and develop safe and effective pharmacological treatments for cannabis-related disorders (CRDs). In particular, we propose to directly address the persistent disorders of cannabis abuse and dependence by synthesizing and pharmacologically evaluating candidate medications that can be further developed into useful pharmacotherapies. Currently, there is no accepted medication for cannabis abuse and dependence, and the most widely studied cannabis-antagonist, SR 141716A (Rimonabant(r)), is being developed instead for the treatment of smoking behavior and obesity. Moreover, like all other available cannabis-antagonists, SR 141716A is not a neutral antagonist but, rather, an inverse agonist with direct behavioral effects. Therefore, we plan to address the need for novel and safe medications by synthesizing and pharmacologically identifying highly selective, neutral CB-1 antagonists. We are targeting neutral antagonists because this type of compound should be less handicapped than inverse agonists by direct behavioral effects. Consequently, neutral antagonists may be especially useful for helping cannabis-addicted individuals withdraw from drug use and avoid relapse. In our preliminary studies, we already have successfully synthesized a selective CB-1 antagonist that is silent in functional biochemical tests of either agonist or inverse agonist activity. In our proposed research, we will continue to use our unique chemical templates for cannabinoid ligands to design and construct novel molecules. Our goal will be to generate both short-acting and long-acting compounds that we believe may be neutral antagonists. Our strategy will be to conduct side-by-side comparisons with the inverse agonist SR 141716A whenever possible. Compounds that meet biochemical criteria for neutral antagonism will be studied in rats to confirm their biological activity as antagonists of CB-1 induced catalepsy and to separate active compounds on the basis of the duration of their behavioral effects. Additionally, we will determine whether they serve as neutral antagonists of the effects of both CB-1 agonists and inverse agonists on operant behavior. Next, the most successful novel drugs will be assessed for their antagonism of the discriminative-stimulus and reinforcing effects of ZX9THC, which are preclinical indices of its abuse-related effects. In the latter studies, we also will determine the effectiveness with which these novel drugs forestall the re-initiation of drug-seeking behavior that can be elicited by free injections of delta9THC or contextually-associated stimuli. Finally, we will directly examine the effects of neutral antagonists in delta9THC-dependent subjects at differing time points following drug injection. These last studies, though experimentally arduous, will provide critical information regarding the appropriate use of CB-1 antagonists in the treatment of delta9THC-dependent people. Overall, our proposed studies will permit highly significant progress toward the development of novel antagonist-based medications to combat the addictive power of delta9THC.